Despite the therapeutic promise of stem cell aggregates in bone regeneration, clinical outcomes remain unstable due to the complex and incompletely understood fate of transplanted cells. Here, we investigated the role of programmed cell death in this process, moving beyond the established paradigm of apoptosis. Our study demonstrates that stem cell aggregates (CAs) from human exfoliated deciduous teeth (SHEDs) implanted into a murine femoral defect model undergo necroptosis in a time-dependent manner. Pre-induction of necroptosis in CAs prior to transplantation profoundly impaired bone repair, significantly reducing new bone formation, osteogenic differentiation, and vascularization at the defect site. Conversely, pharmacological inhibition of necroptosis using Necrostatin-1 rescued the regenerative capacity. Crucially, we identified that this inhibitory effect is primarily mediated by extracellular vesicles released during necroptosis (Nec-EVs). Inhibition of Nec-EV biogenesis with GW4869 restored bone healing. Characterization confirmed the successful isolation of phosphorylated mixed lineage kinase domain-like protein (pMLKL)-enriched Nec-EVs. Proteomic analysis revealed a distinct cargo profile in Nec-EVs, notably enriched in proteins involved in translation regulation and RNA metabolism. Functionally, Nec-EVs directly suppressed the proliferation and osteogenic potential of bone marrow stem cells (BMSCs) in vitro, and their local application in vivo was sufficient to recapitulate the impaired bone regeneration phenotype. Collectively, this work establishes necroptosis and its associated vesicular signaling as novel detrimental axes in cell-based bone regeneration, providing mechanistic insights and potential therapeutic targets for enhancing the reliability of regenerative therapies.

Chronic diabetic wounds represent a significant clinical challenge due to impaired healing processes characterized by persistent inflammation, compromised angiogenesis, and a hostile microenvironment. Despite the therapeutic potential of mesenchymal stem cells (MSCs), their post-transplantation survival remains suboptimal in such pathological conditions. Here, we developed a sustained-release oxymatrine-loaded hyaluronic acid methacryloyl (HAMA) hydrogel to enhance placental mesenchymal stem cell (PMSC)-mediated repair in diabetic wounds. In a streptozotocin-induced diabetic mouse model with full-thickness dorsal skin defects, photo-crosslinked HAMA-OMT hydrogels were fabricated and evaluated for their effects on PMSC survival and wound healing outcomes. Comprehensive assessments included wound closure rates, histological analysis, angiogenesis, collagen remodeling, macrophage polarization, and the activation status of Nrf2/HO-1 and TLR4/NF-κB signaling pathways. The porous HAMA matrix provided structural support for PMSC adhesion and survival, while OMT incorporation improved hypoxia resistance and mitigated burst release kinetics. In diabetic wounds, the HAMA-OMT+PMSCs combination treatment significantly accelerated re-epithelialization, enhanced regeneration of hair follicles and sweat glands, promoted angiogenesis, and improved collagen organization compared to single-treatment groups. Mechanistically, OMT exerted dual regulatory effects by suppressing TLR4/NF-κB-driven inflammatory responses, promoting CD206+M2 macrophage polarization, and activating Nrf2/HO-1-mediated antioxidant defenses, thereby protecting PMSCs from oxidative stress-induced apoptosis. Collectively, these findings demonstrate that OMT-loaded HAMA hydrogel synergizes with PMSCs to reconstruct a pro-regenerative microenvironment, offering a promising cell, material, and small-molecule combinatorial strategy for the effective treatment of chronic diabetic wounds.

Hemoporfin-mediated photodynamic therapy (HMME-PDT) has demonstrated significant advantages in the treatment of Port-wine stains (PWSs). However, the therapeutic efficacy of HMME-PDT remains suboptimal in a subset of patients. Somatic mosaic mutations in GNAQ (c.548G>A, p. R183Q) are frequently detected in endothelial cells (ECs) of lesions and represent a common pathogenic mechanism. In this study, we successfully established an in vitro model of PWSs by introducing the GNAQ p. R183Q mutation into HUVECs using lentiviral infection. Our results revealed that GNAQ p. R183Q mutation enhanced ECs proliferation, migration, and angiogenesis. Moreover, the mutation augmented anti-apoptotic mechanisms, thereby conferring heightened resistance to HMME-PDT-induced apoptosis. Residual angiogenic activity persisted following HMME-PDT treatment. These effects are likely mediated by activation of the angiopoietin-2 (ANGPT2)/TIE2/PI3K/AKT signaling axis. Knockdown of ANGPT2 partly reversed these phenotypic alterations and significantly enhanced the efficacy of HMME-PDT. The combination of HMME-PDT with anti-ANGPT2 therapy holds promise for enhancing therapeutic efficacy, suppressing pathological angiogenesis, and ameliorating the clinical manifestations of PWSs.

Type 2 diabetes mellitus (T2DM) disrupts bone metabolism, exacerbating craniomaxillofacial bone loss and impairing the efficacy of regenerative therapies. While mesenchymal stromal cell (MSC)-based approaches, including MSC-derived cell aggregates (CAs), have shown promise in tissue regeneration across multiple organs, their regenerative capacity is significantly compromised in recipient diseased microenvironments. Here, using a high-fat diet (HFD)-induced T2DM murine model, this study reveals that CA implantation fails to boost osteogenesis or restore mandibular bone defects in diabetic mice due to systemic metabolic dysregulation. To address this limitation, we propose a combinatorial strategy integrating CAs with recipient periodic fasting, a metabolic intervention shown to alleviate lipidemia thus creating a beneficial condition for regeneration. Remarkably, the combined therapy enhances osteogenesis and safeguards mandibular bone regeneration in diabetic mice, evidenced by increased trabecular bone volume, reduced trabecular spacing, and elevated RUNX2 expression in defect areas. This combinatorial approach overcomes the limitations of standalone MSC therapies, highlighting the importance of addressing both local tissue repair and systemic metabolic dysregulation in diabetic bone regeneration. The findings propose a novel strategy integrating cellular engineering with metabolic interventions to optimize tissue regeneration in T2DM-related complications, offering translational potential for improving dental rehabilitation in diabetic patients.

Doxorubicin (DOX), a potent anthracycline chemotherapeutic agent, is widely used in cancer treatment but is associated with significant adverse effects, particularly DOX-induced cardiomyopathy (DIC). DIC pathogenesis involves the generation of reactive oxygen species (ROS) and ferroptosis induction. Novel therapeutic strategies targeting antioxidant defenses and ferroptosis inhibition are essential for mitigating DIC. An innovative bimetallic metal-organic framework (MOF), NiCu-MOF (NCM), is developed, exhibiting multifaceted antioxidant enzyme-mimicking activities that effectively scavenge a broad spectrum of ROS. Additionally, the bimetallic NCM exhibits excellent iron-chelating ability. In vitro experiments demonstrate that NCM significantly reduces cardiomyocyte death by attenuating ROS levels and inhibiting ferroptosis. Furthermore, in a mouse model of DIC, NCM treatment results in substantial myocardial protection, evidenced by improved cardiac function and structural integrity. This protective effect is attributed to suppression of ferroptosis, preservation of mitochondrial function, and attenuation of inflammatory responses. Collectively, these findings highlight biocompatible NCM's potential as a novel cardioprotective agent and offer a promising therapeutic strategy for managing DIC.

Objective: This study aimed to explore the impact of fear of cancer recurrence on anxiety and depression in female cancer patients, and to examine the chain mediating roles of financial toxicity and psychological distress in this relationship. Methods: Between February and July 2024, a total of 417 female cancer patients from top-tier cancer hospitals across 13 regions in China were recruited. Participants completed the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS), the Comprehensive Score for Financial Toxicity (COST), and the Distress Thermometer (DT). Results: (1) Fear of recurrence, financial toxicity, psychological distress, anxiety, and depression were significantly correlated. (2) Two mediating pathways were identified: a direct path where fear of recurrence increased psychological distress, leading to heightened anxiety and depression; and an indirect chain mediation path wherein fear of recurrence elevated financial toxicity, which in turn intensified psychological distress, ultimately contributing to anxiety and depression. Conclusions: Health care providers should be aware of the psychological and financial burdens associated with fear of recurrence in women with cancer. Addressing these issues may enhance the effectiveness of psychological interventions, reduce emotional distress, and ultimately improve patients'quality of life.

Introduction The dental follicle localizes the surrounding enamel organ and dental papilla of the developing tooth germ during the embryonic stage. It can differentiate and develop to form the periodontal ligament, cementum, and alveolar bone tissues. Postnatally, the dental follicle gradually degenerates, but some parts of the dental follicle remain around the impacted tooth. However, the specific cellular components and the intricate regulatory mechanisms governing the postnatal development and biological function of the dental follicle have not been completely understood. Methods We analyzed dental follicles with single-cell RNA sequencing (scRNA-seq) to reveal their cellular constitution molecular signatures by cell cycle analysis, scenic analysis, gene enrichment analysis, and cell communication analysis. Results Ten cell clusters were identified with differential characteristics, among which immune and vessel-related cells, as well as a stem cell population, were revealed as the main cell types. Gene regulatory networks (GRNs) were established and defined four regulon modules underlying dental tissue development and microenvironmental regulation, including vascular and immune responses. Cell–cell communication analysis unraveled crosstalk between vascular and immune cell components in orchestrating dental follicle biological activities, potentially based on COLLAGAN-CD44 ligand–receptor pairs, as well as ANGPTL1-ITGA/ITGB ligand–receptor pairs. Conclusion We establish a landscape of cell regulatory and communication networks in the human dental follicle, providing mechanistic insights into the cellular regulation and interactions in the complex dental follicle tissue microenvironment.

Background: Type 2 diabetes (T2D) is a global metabolic condition associated with complications of multiple organs, including the bone. However, the exact impact of T2D on bone along the disease progression, particularly in the early phase, remains largely unknown. Methods: Four-week and sixteen-week high-fat diet (HFD) feeding-induced T2D mouse models were established, and the glucose metabolic status was examined. Bone mass was evaluated by micro-computed tomography (micro-CT), and immunofluorescent (IF) staining was performed for bone histomorphometry with enzyme-linked immunosorbent assay (ELISA) determining serum markers. RNA sequencing analysis was performed to examine the transcriptome of bone, and single-cell RNA-sequencing (scRNA-seq) analysis was further applied. Bone marrow mesenchymal stem cells (BMMSCs) were isolated and analyzed for functional behaviors. Results: The occurrence of glucose metabolic disorders was confirmed at both four weeks and sixteen weeks of HFD feeding, showing increased blood glucose levels with impaired glucose tolerance and insulin sensitivity. Notably, early T2D osteoporosis symptoms were detected at four weeks, especially in the trabecular bone, demonstrating reduced bone mass and mineral density. Histological analysis confirmed that bone remodeling and immune-related inflammation were also altered in T2D mice, remarkably at the early phase, mainly reflected by suppressed bone formation, stimulated bone resorption, increased macrophages, and elevated tumor necrosis factor-alpha (TNF-α) levels. Transcriptomic sequencing further demonstrated significant yet distinct changes in the gene expression profile of bone during T2D progression, which confirmed the histological findings. Notably, overlapping genes with altered expression at four weeks and sixteen weeks of T2D compared to the respective control were identified, and bone marrow scRNA-seq analysis indicated many of them were expressed in BMMSCs, suggesting BMMSCs critically involved in T2D osteoporosis. Dysregulated molecular profiles and functional abnormalities of BMMSCs in T2D mice were validated by ex vivo assays, showing early and persistent occurrence of impaired colony-forming and proliferative capacities with biased differentiation potential. Conclusions: These findings elucidate the bone lesion phenotype in T2D, particularly at the early phase, uncover changes in gene expression profiles of bone during T2D progression, and clarify the functional alterations in bone stem cells, providing a basis for subsequent research and the development of treatment strategies.

Ethnopharmacological relevance Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. Aim of the study To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. Methods The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. Results In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. Conclusion Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA+ dental follicle stem cells (DFSCs) and CD31+ Endomucin+ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA+ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA+ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.

Periodontal disease is a major contributor to tooth loss worldwide in adults. Particularly, periodontal bone defect is a common clinical condition, yet current therapeutic strategies exhibit limited effectiveness. Recently, natural bone graft materials have attracted considerable interest for enhancing bone defect repair due to their superior biocompatibility and osteogenic capabilities. Nevertheless, clinically applicable human-derived biomaterials to boost bone regeneration are currently not accessible. Here, enlightened by the decellularization technique, we successfully prepared the human decellularized alveolar bone and tooth dentin tissues from healthy individuals and obtained micro-sized bioactive decellularized extracellular matrix (dECM) particles for treatment of periodontal bone defects. After characterizing the two representative dECM tissues and particles by multiple physiochemical approaches, we revealed that both human decellularized alveolar bone matrix particles (hDABMPs) and human decellularized tooth dentin matrix particles (hDTDMPs) possessed excellent biocompatibility. Furthermore, both biomaterials significantly enhanced the proliferation and osteogenic differentiation of human dental follicle stem cells, potentially contributing to periodontal bone formation. Indeed, in a rat model, both types of dECM microparticles were found to facilitate tissue regeneration at periodontal bone defect sites, demonstrating comparable efficacy for promoting bone defect repair. Collectively, this study provides an important basis for clinical exploration of natural human-derived micro-sized biomaterials for periodontal bone defect repair and opens a new path for periodontal disease treatment strategies.

Lung cancer is a leading cause of cancer-related mortality worldwide, profoundly affecting patients' quality of life. Patient-reported outcomes (PROs) provide essential insights from the patients' perspective, a crucial aspect often overlooked by traditional clinical outcomes. This review synthesizes research on the role of PROs in lung cancer surgery to enhance patient care and outcomes. We conducted a comprehensive literature search across PubMed, Scopus, and Web of Science up to March 2024, using terms such as "lung cancer," "Patient Reported Outcome," "lobectomy," "segmentectomy," and "lung surgery." The criteria included original studies on lung cancer patients who underwent surgical treatment and reported on PROs. After screening and removing duplicates, reviews, non-English articles, and irrelevant studies, 36 research articles were selected, supported by an additional 53 publications, totaling 89 references. The findings highlight the utility of PROs in assessing post-surgical outcomes, informing clinical decisions, and facilitating patient-centered care. However, challenges in standardization, patient burden, and integration into clinical workflows remain, underscoring the need for further research and methodological refinement. PROs are indispensable for understanding the quality-of-life post-surgery and enhancing communication and decision-making in clinical practice. Their integration into routine care is vital for a holistic approach to lung cancer treatment, promising significant improvements in patient outcomes and quality of care.

Background Vascular dementia (VaD) is a heterogeneous disorder with distinct subtypes, each exhibiting unique neuropathological profiles. Although neuroimaging studies have identified some subtype-specific structural brain alterations, a systematic investigation establishing causal relationships between imaging-derived phenotypes (IDPs) and the development of specific VaD subtypes remains absent from current literature. Methods Two-sample Mendelian Randomization (MR) analyses were conducted to assess causal relationships between 3,935 brain IDPs from UK Biobank neuroimaging and four VaD subtypes (multiple infarctions, subcortical, sudden onset, and mixed) from FinnGen. Significant findings from the primary inverse variance weighted analysis were validated using Bayesian Weighted MR (BWMR) and MR Robust Adjusted Profile Score (MR-RAPS) methods to mitigate potential pleiotropy. Sensitivity analyses and reverse MR assessed robustness and directionality. Results Initial analyses identified highly significant causal associations for 33, 27, 25, and 30 brain IDPs with multiple infarctions, subcortical, sudden onset, and mixed VaD subtypes, respectively. Validation with BWMR and MR-RAPS confirmed 22, 17, 17, and 21 robustly causal IDPs for each subtype. Key findings included causal roles for gray matter volume/surface area changes in cognition-related regions specific to each subtype, as well as axonal and myelin damage with distinct anatomical localization in each subtype. Reverse MR found no evidence that any VaD subtype causally influenced the identified brain IDPs. Conclusion Our study provides robust genetic evidence for distinct causal relationships between specific patterns of brain structural alterations and different VaD subtypes. These subtype-specific neuroimaging signatures highlight divergent neuroanatomical substrates underlying VaD heterogeneity and offer potential targets for developing diagnostic biomarkers.

Type 1 diabetes (T1D) is a complex autoimmune disorder distinguished by the infiltration of immune cells into pancreatic islets, primarily resulting in damage to pancreatic beta-cells. Despite extensive research, the precise pathogenesis of T1D remains elusive, with its etiology linked to a complex interplay of genetic, immune, and environmental factors. While genetic predispositions, such as HLA and other susceptibility genes, are necessary, they do not fully account for disease development. Environmental influences such as viral infections and dietary factors may contribute to the disease by affecting the immune system and epigenetic modifications. Additionally, endogenous retroviruses (ERVs) might play a role in T1D pathogenesis. Current therapeutic approaches, including insulin replacement therapy, immune omodulatory therapy, autoantigen immunotherapy, organ transplantation, and genetic modification, offer potential to alter disease progression but are still constrained by limitations. This review presents updated knowledge on T1D, with a focus on risk factors, predisposing hypotheses, and recent advancements in therapeutic strategies.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer and is highly malignant. Despite advances in diagnostics and treatment, the prognosis for ccRCC remains poor. The dual nature (promotion or inhibition) of S100A2 in different cancer types shows the complex involvement of its tumorigenesis, but its effect in ccRCC remains unclear. In this study, we first elucidate the tumor-promoting function of S100A2 in ccRCC by reprogramming glycolysis. Mechanistically, we demonstrate that S100A2 accelerates cancer progression through its interaction with the transcription factor HNF1A, leading to activating GLUT2 transcription. The upregulation of GLUT2 significantly enhances glucose uptake by cancer cells, thereby fueling augmented glucose metabolism and fostering the malignant progression of ccRCC. Collectively, our findings highlight the pivotal role of the S100A2-HNF1A-GLUT2 axis in promoting migration and invasion of ccRCC by amplifying glycolysis and suggest that targeting the S100A2-HNF1A-GLUT2 axis is clinically relevant for the treatment of metastatic ccRCC.

Harnessing natural developmental programs to repair and replace damaged organs represents promising approaches in regenerative medicine. However, effective strategies are still lacking for tissue regeneration in complicated conditions, such as the periodontal bone defect. Here, human dental follicle stem cells (hDFSCs) and their aggregates (hDFSCA) are cultured and characterized, which are formed based on the inherent property of these stem cells self-assembly into compact spheroid-like structures, mimicking mesenchymal condensation in development. A periodontal tissue-specific microenvironment simulation material is then established, human decellularized alveolar bone matrix particles (hDABMPs), which possess favorable physicochemical and biological properties for regenerative use. hDFSCs co-cultured with hDABMPs exhibit improved cell function, and hDFSCA-hDABMP co-aggregates are subsequently constructed, which activate the developmental gene expression in hDFSCA and initiate hypoxic adaptation mechanisms for tissue regeneration. Indeed, hDFSCA-hDABMP co-aggregates significantly promote regeneration after implantation in alveolar bone defects with good biosafety. Interestingly, during the early stages of implantation, hDABMPs enhance hDFSC survival and expansion, thereby providing a sufficient source of cells for tissue regeneration. Collectively, this study reveals a development-inspired, engineered cell-niche co-aggregation strategy for enhancing CA therapeutic potential by simulating tissue-specific microenvironments, offering novel insights for functional tissue regeneration.

Endogenous retroelements play vital roles in sustaining immune homeostasis. Activation of endogenous retroelements can trigger cGAS/STING pathway and downstream pro-inflammatory cytokine production. Activated macrophages (M1), which can be induced by pro-inflammatory cytokines, are involved in the development of colitis. Here we aimed to determine whether a retrovirus reverse transcriptase inhibitor azidothymidine (AZT) could influence M1 macrophage polarization and rescue colitis by inhibiting the reverse transcription of murine endogenous retroelements. A dextran sodium sulfate salt (DSS)-induced colitis mouse model (male C57BL/6N) and a lipopolysaccharides-treated RAW264.7 cell line were used to evaluate the protective role of AZT in colitis alleviation. An upregulated expression of endogenous retroelements was first detected in both the colons of the mice with colitis and the lipopolysaccharides-stimulated M1 cells, and treatment with AZT significantly decreased the expression. Meanwhile, a downregulation of cGAS/STING/NF-κB pathway and pro-inflammatory cytokines that induce M1 macrophage polarization was also observed in AZT-treated colitis or M1 groups. Moreover, the symptoms of DSS-induced colitis could be significantly alleviated by AZT. In summary, the endogenous retroelement inhibitor AZT could rescue the DSS-induced colitis possibly via blocking M1 macrophage polarization through cGAS/STING/NF-κB pro-inflammatory pathway. Thus, a pharmacological blockade of endogenous retroelements would be a new strategy for clinical therapy of colitis.

Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia (MCM), characterized by highly variable triglyceride levels with acute episodes of severe hypertriglyceridemia (HTG), are caused by rare variants in genes associated with the catabolism of circulating lipoprotein triglycerides, mainly including LPL, APOC2, APOA5, GPIHBP1, and LMF1. Among them, the LMF1 gene only accounts for 1%. This study described a Chinese patient with severe HTG carrying compound heterozygous variants of a rare nonsense variant p.W168X in exon 3 and a missense variant p.R416Q in exon 9 in the LMF1 gene. These heterozygous variants account for his family's decreased lipase activity and mass, which caused the FCS phenotype.

Huperzine A (Hup A), an extract from Huperzia serrata, exerted its anti-inflammation and anti-oxidation effect to protect against neurodegenerative disorders and organ injury. Ferroptosis was indicated to involve in the development of acute lung injury (ALI) accompanying by lipid reactive oxygen species (ROS) overexpressed. However, there is little research focused on the protective effect of Hup A on ALI, and the underlying molecular mechanism remains elusive. This study aims to determine the therapeutic effect of Hup A on ALI in vivo and in vitro. Hup A attenuated lung injury and cellular damage in lipopolysaccharide-induced ALI (LPS-ALI) models, both in vivo and in vitro, accompanied by the upregulation of ferroptosis-associated proteins (SLC7A11 and GPX4). Furthermore, the pretreatment with Hup A decreased the abundance of inflammation factors (IL-6, TNF-α), MDA, lipid ROS, and Fe2+ in the LPS-ALI model, while it also promoted the secretion of SOD and GSH to antagonize peroxidation. Mechanistically, RNA sequencing and network pharmacological analysis synergistically revealed the PI3K/Akt signaling pathway as a potential target of Hup A. In vitro experiments demonstrated that Hup A effectively activated GPX4 through the PI3K/Akt signaling pathway, which was subsequently reversed by LY294002, an inhibitor of the PI3K/Akt signaling pathway. Consequently, our results revealed that Hup A inhibited ferroptosis in LPS-ALI by activating the PI3K-Akt signaling pathway which indicated the potential therapeutical effect of Hup A and further emphasized the pivotal role of ferroptosis in ALI.